It has been assumed for some time that the primary source of the antitumor activity of the fluorinated pyrimidines is the inhibition of thymidylate synthetase and the subsequent inhibition of DNA synthesis. However, several of these compounds are known to be potent inhibitors of ribosomal RNA maturation in both procaryotes and eucaryotes. Since the synthesis of ribosomes during the G1 phase of the cell cycle is a prerequisite for DNA synthesis during the S phase, the inhibition of ribosomal RNA maturation by the fluorinated pyrimidines may be of equal, or even greater, importance than the inhibition of DNA synthesis. The objective of the proposed research is to determine the relative importance of the inhibition of ribosomal RNA maturation in the overall cytotoxic activity of 5-fluorouridine and 5-fluoro-2'-deoxyuridine in Novikoff hepatoma cells. This will be accomplished by treating cells with these drugs under various experimental conditions and following simultaneously cell growth, ribosomal RNA maturation, and DNA synthesis. The information obtained could provide new insights for the design of more effective therapeutic regimens or combination drug therapy. Knowledge of the exact sites of inhibition and the cell cycle specificity will help clinicians take full advantange of cytotoxic potential of these drugs. BIBLIOGRAPHIC REFERENCES: Wilkinson, D. S., Solomonson, L. P. and Cory, J. G., "Increased Thymidylate Synthetase Activity in 5-Flourodeoxyuridine-Resistant Novikoff Hepatoma Cells," Proc. Soc. Exptl. Biol. Med. 154 (1977), in press. Cory, J. G., Crumley, J. and Wilkinson, D. S., "Evidence for Role of Purine Nucleoside Phosphorylase in Sensitivity of Novikoff Hepatoma Cells to 5-Fluorouracil," Adv. Enz. Reg. 15 (1977), in press.